Pulmonary arterial hypertension (PAH) is a rare, rapidly progressive and fatal disease that is characterized by pulmonary arterial remodeling, severe pulmonary hypertension, and progressive right heart failure. The prognosis of PAH is poor with an approximate 15% mortality within 1 year on modern therapy. Over the past two decades, a number of medications for the treatment of PAH have been shown to improve patient symptoms and exercise capacity; however, none of the current treatments are curative and long-term prognosis remains poor. There remains a high unmet need for novel PAH targets and therapies that reverse the disease process and improve long-term health outcomes. Vasoactive intestinal peptide (VIP) is a 28 amino acid peptide hormone that activates VPAC1 and VPAC2 receptors in the pulmonary vasculature and has been shown to relax pulmonary vascular smooth muscle, neutralize pulmonary vasoconstrictors, and inhibit pulmonary vascular smooth muscle cell proliferation. Additionally, VIP improves right heart systolic and diastolic function and has broad anti-inflammatory and anti-fibrotic actions. VIP has been shown to be effective in reversing pulmonary vascular remodeling and prolonging survival in a murine model of PAH. PB1046is a recombinant acid fusion protein comprising biologically active VIP at the N-terminus and a physiologically inert repeating polymeric elastin-like peptide (ELP) at the C-terminus. The fusion of VIP to the ELP moiety significantly increases in vivo exposure through sustained release from the injection site, extended circulatory half-life and protection from enzymatic degradation. PB1046 is active as a fusion protein, i.e. the VIP moiety activates the receptor without a requirement to be cleaved or released from the ELP biopolymer. PhaseBio has tested PB1046 in a single-dose Phase 1 study in which the PK and PD enhancement of VIP via the ELP fusion was clearly demonstrated in the observed week-long PB1046 exposure profile and systolic blood pressure lowering effect after a single-dose in essential hypertension patients. Importantly, PB1046 demonstrated a clean single-dose safety/tolerability profile across the expected therapeutic dose range. In this SBIR Fast-Track proposal, we are applying for funding for the Phase 1b and Phase 2 studies of PB1046 in patients with PAH. PhaseBio will investigate the multi-dose safety, PK, and PD of PB1046 in an open-label, non- placebo controlled, multi-dose Phase 1b study of PB1046 in PAH patients who have an implanted pulmonary arterial pressure monitor (cardioMEMS). In this initial study, PB1046 will be administered as once weekly subcutaneously injections x 4 weeks at a dose level previously tested and shown to be safe and well tolerated in subjects from the single-dose Phase 1 study and in an ongoing Phase 1 multiple ascending dose study in ambulatory heart failure patients. When the safety, PK, and PD profile of PB1046 are confirmed in PAH subjects, a randomized, double-blind, placebo controlled Phase 2 study of PB1046 will be initiated to investigate the potential beneficial effects of PB1046 on exercise capacity and hemodynamics in symptomatic PAH patients.